Cancerous tumors are currently one of the most severe diseases that endanger the lives and health of the world population. According to the World Health Organization (WHO), statistics show that there are 16 million incidences of cancer in the world each year causing the death of about 600 million people and is the second leading cause of death ranked only under cardiovascular diseases. There are more than 70 types of anti-tumor drugs marketed worldwide in total and the number is rapidly growing at 1-2 new drugs per year. However, in China, the development of anti-tumor drugs is still at an infancy stage; for economic and supply reasons, majority of tumor patients still do not receive treatment with advanced drugs. The development of novel anti-tumor drugs with autonomous intellectual property rights is therefore of great significance to the country's developments in economy and healthcare. Camptothecin (CPT) is a kind of alkaloid isolated from Camptotheca acuminata of the Nyssaceae Family. It acts to inhibit DNA topoisomerase I. Due to its low specificity, camptothecin results in hematuria and bone marrow suppression which limit its further application. Semi-synthetic camptothecin derivatives, after structural modification, have increased specificity, lower toxicity, and improved efficacy. Currently, camptothecin drugs available in both domestic and foreign markets include irinotecan (CPT-11), topotecan, 10-hydroxy camptothecin and belotecan (CKD-602) which became available in 2004. Other camptothecin drugs which have undergone clinical trials include NP-1350 (karenitecin), gimatecan, chimmitecan, etc.
Irinotecan is the most successful camptothecin derivative resulting from structural modification. It has broad-spectrum anti-tumor effects and, since 5-fluorouracil 40 years ago, is the only first-line drug to be used for treatment of metastatic colorectal cancer while also being used in treatment of lung cancer, ovarian cancer, breast cancer, stomach cancer and pancreatic cancer. Topotecan is the worst camptothecin derivative resulting from structural modification. Preclinical evaluation shows that it is ineffective for most tumors and, clinically, it could only be used for treating small cell lung cancer which is known to be most responsive to chemotherapy. Even so, the remission time is short and the effect is poor.
Camptothecin is a pentacyclic alkaloid which is amenable to a variety of structural modifications at the C-7, 9- and 20 positions. Highly efficacious compounds of low toxicity can be obtained when structural modifications are made at the C-7 and 9 positions. For examples, ethyl group was introduced to irinotecan at C-7; N-t-butyloxymethyloxime group was introduced to gimatecan at C-7; said group is lipophilic and can pass through the blood brain barrier. Gimatecan is undergoing clinical trials for treatment of glioma. Chimmitecan, with propenyl group introduced at C-9, also has good anti-tumor effect. However, topotecan, with dimethylaminomethyl introduced at C-9, did not demonstrate an increase in efficacy and reduced toxicity, and in fact, its toxicity increased in comparison to 10-OH-CPT. The only improvement was its solubility. Therefore, any improvement in activity of the compounds by the introduction of chemical groups at C-7 or C-9 positions is determined by the nature of the group that is introduced.
